Migraine is a paroxysm of headache lasting 4 to 72 hours, which is accompanied by nausea, vomiting, extreme sensitivity to light and sound, and the like [Merck Manual, 17th Edition, Section 168; Therapeutic Guideline of Japanese Society of Neurology (Societal Neurologica Japonica); International Classification of Headache Disorders-II: ICHD-II, 2004]. As one of pathophysiology of migraine and the underlying mechanisms, vasodilation of extra- and/or intra-cranial blood vessels including superficial temporal artery has been proposed [Arch. Neurol. Psychiatr., vol. 39, p. 737-763 (1938); Cephalalgia, vol. 1, p. 143-147 (1981); Naika (Internal Medicine), vol. 81, p. 601-609 (1998); Naika, vol. 81, p. 639 (1998)]. It has also been known that the hydrophilic agonists of serotonin receptor 5-HT1 (5-hydroxytryptamine 1) such as ergot alkaloid and sumatriptan, which poorly cross the blood brain barrier, are effective for the treatment of migraine since they can contract the dilated cranial blood vessels via the serotonin receptor 5-HT1 of cerebral artery [Ann. N.Y. Acad. Sci., vol. 600, p. 587-600 (1990); Neurology, vol. 43, p. S43-S47 (1993)].
Thus, it has been assumed that migraine could be treated by suppressing vasodilation of the extra- and/or intra-cranial blood vessels.
On the other hand, it has also been reported that the adenosine concentrations in the plasma of patients suffering from migraine are increased at an average of 68% at one hour after the migraine attack compared with those in crisis-free periods, that activation A2 receptors by adenosine causes a dose-dependent serotonin uptake by platelets and consequently the vasodilation is induced by rapid reduction of serotonine [Can. J. Neurol. Sci., vol. 2, p. 55-58 (1998)], and that intravenous injection of the adenosine potentiator to patients suffering from migraine induces the migraine attack [Med. J. Aust., vol. 162, p. 389-390 (1995)]. In addition, it has been known that adenosine has a potent vasodilating action and that an adenosine A2A receptor and an adenosine A2B receptor are involved in the vasodilation during the migraine attack and in the vasodilation induced by adenosine [Am. J. Physiol. Heart Circ. Physiol., vol. 280, p. 2329-2335 (2001)]. In view of these facts, it has been considered that migraine could be treated by suppression of vasodilation induced by adenosine.
It has also been known that caffeine has an adenosine antagonistic action with low specificity and acts to relieve migraine headache, though caffeine induces drug dependence as a side effect and causes a caffeine-withdrawal headache [ref.: Pain, 1991; vol. 44, p. 151-155; and Drugs, 1998, vol. 49, p. 37-50].
Pyrazole derivatives with adenosine antagonistic activity (WO97/01551), adenosine A1 receptor agonists such as GR79236 (ref: Cephalalgia, 2002, vol. 22, p. 260-264), and the like are known to have a therapeutic effect for migraine.
On the other hand, many of xanthine derivatives including the compounds represented by the formula (I) as mentioned below have been known to have, for example, adenosine A2 receptor antagonistic action, anti-Parkinsonian action, central nerve exciting action, suppressive action on neurodegeneration, antidepressive action, anti-asthma action, suppressive action for bone resorption, hypoglycemic action, suppressive action for thrombocytosis, and the like [Japanese Published Examined Patent Application No. 26516/1972, Japanese Published Unexamined Patent Application No. 211856/1994, Japanese Published Unexamined Patent Application No. 239862/1994, Japanese Published Unexamined Patent Application No. 16559/1994, WO92/06976, WO94/01114, WO95/23165, WO99/12546, WO99/35147; J. Med. Chem., vol. 34, p. 1431 (1991); J. Med. Chem., vol. 36, p. 1333 (1993)].